Postinfluenza bacterial pneumonia: host defenses gone awry

Abstract

Influenza is a common respiratory pathogen causing both seasonal and pandemic disease. Influenza infection predisposes the host to secondary bacterial infection of the respiratory tract, which is a major cause of both morbidity and mortality in flu-related disease. In this review, we will discuss innate and adaptive antiviral responses during influenza infection, and review how these responses modulate protective immunity against secondary bacterial pathogens of the lung. Specific emphasis will be placed on implications of bacterial superinfection and mechanisms involved.

FIG. 1.

Effects of influenza virus on respiratory epithelium promoting bacterial adherence. In a normal resting respiratory epithelium (A), airway and AECs provide a protective barrier between the airway/airspace and the lung interstitium. Airway epithelial cells express cilia, which aid in the proximal movement of cellular debris and other secreted substances from the distal airway and airspace. (B) Influenza virus (triangle) infects epithelial cells by binding of the viral hemagglutinin to the sialic acid residues on the host cells, resulting in the endocytosis of virus. Recruited T cells, exudate macrophages, and neutrophils can control influenza infection, but may also cause collateral damage leading to apoptosis of respiratory epithelium, exposure of the basement membrane components, and the appearance of basal progenitor cells to replace damaged epithelium. Proinflammatory cytokines produced in response to influenza induce upregulation of platelet-activating factor (PAF) receptors on airway and alveolar epithelial cells (black rectangle). During bacterial superinfection (C), Streptococcus pneumoniae (circle) and other bacterial species bind to PAF receptors and other glycoproteins (gray rectangle) made accessible or modified on epithelium, basement membrane, or basal progenitor cells after influenza infection. Additionally, influenza can promote loss of ciliary number and/or function, leading to decreased mucociliary transport capacity, further contributing to bacterial superinfection.

FIG. 2.

Dysregulation of cytokines and chemokines during primary influenza infection followed by secondary bacterial superinfection. Schematic showing the complex interactions between cytokines and chemokines that activate (arrow) or inhibit (block) cellular effectors important in host defense against bacterial pathogens. Established pathways are illustrated by solid lines, whereas speculative pathways are shown in dashed lines.